Encapsulation of oleophilic substances and compositions produced thereby

ABSTRACT

Multiple micro-encapsulations of a high concentration oleophilic substance using heat to set the primary particle renders the composition suitable for the production of free-flowing powders or beadlets. Microencapsulation involves forming an emulsion out of the oleophilic substance and a polymer, and then use heat setting and/or cross-linking the polymer encapsulates the oleophilic composition. This process is then repeated with a second polymer or third polymer, and with or without cross-linked via the same or different mechanism to further protect the oleophilic substance.

CROSS-REFERENCE APPLICATION

This is a continuation of U.S. Ser. No. 08/439,787, filed May 24, 1995,which is a continuation-in-part of U.S. Ser. No. 08/269,720, filed Jul.1, 1994.

FIELD OF THE INVENTION

The invention relates to encapsulation of oleophilic substances (as usedherein the term "oleophilic" is to embrace fat- and oil-solublesubstances as well as fats and oils), and to compositions produced bythis process. In particular, the invention relates to the preparation ofhigh potency, dry and free-flowing vitamin powders/beadlets usingmultiple microspheric and/or microencapsulation techniques.

BACKGROUND OF THE INVENTION

Oleophilic substances, and in particular fat-soluble vitamins such as A,D, E and K, have had limited incorporation into dry materials because oftheir oil-like nature. Accordingly, oleophilic substances have tended tobe macroencapsulated and delivered as units of coated oil.Unfortunately, however, such delivery drastically restricts theapplications for which these oleophilic substances are suitable. Forexample, current commercial techniques can only produce concentrationsof vitamin E which range up to 50% by weight.

The present invention overcomes the limitations inherent in the priorart encapsulation techniques and allows for production of high potencyvitamins in a free flowing powder form. Such a form allows for deliveryinto multiple vitamin tablets or foods, such as cereal, and provides theadvantages of reducing tablet size or the bulk required for subsequentdelivery. Of particular interest is high potency Vitamin E in whichVitamin E forms greater than about 50% by weight of a dry powder orbeadlet.

The prior art, as represented by Lim, et al., U.S. Pat. No. 4,389,419,issued Jun. 21, 1983, the contents of which are herein incorporated byreference, describes the formation of an emulsion consisting of acontinuous phase aqueous solution of an alkali metal alginate, andoptionally, a water-soluble alcohol-insoluble filler such as apolysaccharide, and a dispersed phase of an oleophilic substance. Theemulsion thus produced is then formed into droplets which are emersedinto an alcoholic solution of multi-valent cations, to produce awater-insoluble shape-retaining alginate matrix filled with precipitatedpolysaccharide and enclosing plural oil droplets.

The Lim, et al. approach differs markedly from that of the subjectinvention in which an oleophilic substance is incorporated into aprimary polymer containing solution, and then solidified under mixingconditions to encapsulate the fat-soluble substance and form anencapsulated fat-soluble composition. Through the use of mixingconditions in forming the primary particle, far greater concentrationsof oleophilic substances relative to those achieved by Lim, et al. canbe realized. As stated by Lim, et al., the amount of oil may range frombetween 1% up to nearly 30%. However, at the higher end of this range,the stability of the Lim, et al. oil-in-water emulsion is decreased andthe quality of the Lim, et al. microcapsule is reduced. Additionally,the Lim, et al. droplets need to be removed from the alcoholic solutionand washed, or otherwise treated, to remove any residual alcohol, thusrequiring extra production steps.

Another markedly different approach employed for encapsulating vitaminor mineral nutrients, such as thiamine, is described by Hall, et al.,U.S. Pat. No. 4,182,778, issued Jan. 8, 1980, the contents of which areherein incorporated by reference. Hall, et al. describes encapsulationby fluidizing the nutrient in a gaseous stream and contacting thenutrient with finely atomized droplets of a coating solution. Nowhere,however, is the application of the Hall, et al. suggested for use witholeophilic substances.

As described below, the concentration of the oleophilic substance in thesubject invention typically ranges from about 30% to about 90% based onthe dry weight percentage of the final encapsulated oleophiliccomposition. These percentages are far superior to those described byLim, et al., and form a major breakthrough over the current state of theart which only allows percentages of vitamin E to reach about 50%. Thus,the subject invention fulfills a long-felt need in the art for a highpotency encapsulated oleophilic composition.

SUMMARY OF THE INVENTION

The invention provides a method for producing a composition whichencapsulates an oleophilic substance. This method comprisesincorporating an oleophilic substance into a primary polymer-containingsolution, and solidifying the primary polymer under mixing conditions toencapsulate the oleophilic substance within the polymer and form thecomposition.

Typically, the primary polymer is a cellulose, such as methylcelluloseand hydroxypropyl methylcellulose, and the oleophilic substance is afat-soluble vitamin, such as vitamin A, D, E, and K. Preferably, theconcentration of the oleophilic substance ranges from about 30% to about90% based on a dry weight percentage of the final encapsulatedcomposition.

Also provided is a preferred method for producing a compositionencapsulating an oleophilic substance. This method involvesincorporating an oleophilic substance into a primary polymer-containingsolution, solidifying the primary polymer under mixing conditions toencapsulate the oleophilic substance within the polymer and form aprimary particle, and adding a secondary polymer under mixing conditionsto further encapsulate at least one primary particle within thesecondary polymer and form the composition (secondary particle). Ofcourse, multiple primary particles may be encapsulated to form a singlesecondary particle, and the mixing conditions may vary between the firstand second encapsulation.

As with the first method, the primary polymer is usually a cellulose,such as methylcellulose and hydroxypropyl methylcellulose. The secondarypolymer is generally a cellulose, cellulose derivative, maltodextrin,such as a maltodextrin having a dextrose equivalent value of about 18,alginate, calcium lactate, acacia, gelatin, such as fish gelatin, ormodified starch, such as hydroxypropyl starch or pregelatinized cornstarch.

Preferred celluloses include methylcellulose and hydroxypropylmethylcellulose, and preferred cellulose derivatives includehydropropylmethyl cellulose phthalate.

In a preferred embodiment, the secondary polymer is used to encapsulatethe primary particle. Such encapsulation may be achieved by changing thepH, by adding a cross-linking agent, by heating, by spray drying, or byother suitable means. Example of cross-linking agents include sugar,acacia, cations, or gelatin.

Further provided by the subject invention are compositions produced bythe above methods.

One composition encapsulating an oleophilic substance comprises anoleophilic substance, a first polymer which encapsulates the oleophilicsubstance to form a primary particle, and a second polymer whichencapsulates at least one primary particle. The choices of primary andsecondary polymers are as described above.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1--An illustration of a powder/beadlet showing themulti-microencapsulation structure formed in one embodiment of thepresent invention.

FIG. 2--A scanning electron micrograph (SEM) of a vitamin E powder(X100).

FIG. 3--SEM of a vitamin E powder (X200).

FIG. 4--SEM of sectioned vitamin E powder (X100).

FIG. 5--SEM of sectioned vitamin E powder (X500).

FIG. 6--SEM of vitamin A-palmitate (X50).

FIG. 7--SEM of vitamin A-palmitate (X200).

FIG. 8--SEM of sectioned vitamin A-palmitate (X300).

FIG. 9--SEM of sectioned vitamin A-palmitate (X500).

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in terms of its preferredembodiments. These embodiments set forth to aid in the understanding ofthe invention, but are not to be construed as limiting. Throughout thespecification, percentages are by weight percent and temperatures are°C., unless noted otherwise.

One inventive aspect of the subject invention is the production of highpotency (generally from about 30 to about 90 weight percent) fat-solublevitamins (such as A, D, E and K) in the form of dry powders and/orbeadlets.

These vitamin powders and/or beadlets can be prepared by (1) emulsifyingvitamin oils (such as vitamins A, D, E or K) in a polymeric solution(such as a cellulose or cellulose derivative), (2) dispersing vitamins(present as crystals) in a polymeric solution to form a suspension, or(3) dissolving and/or diluting fat-soluble vitamins in oil, thenemulsifying the vitamin-oil solution in a polymeric solution to form anemulsion. Typically, the polymeric solution will be an aqueous solution.

Then, after the emulsifying, dispersing, dissolving and/or diluting, theemulsion or suspension is heated to a polymeric setting temperature(typically greater than 50° C.) under mixing conditions to produceprimary particles (e.g., microcapsules and/or microspheres).Alternatively, the polymer can be cross-linked. In each of these threeabove scenarios, the oleophilic substance is present as a liquid duringat least a portion of the processing time, and typically throughoutprocessing.

For ease in describing the subject invention, emulsifying, dispersing,dissolving and diluting will collectively be referred to as"incorporating."

The term "mixing conditions" refers to a state of imparted movement,such as that associated with stirring, shaking, agitating, jumbling,etc., which is vigorous enough to cause the emulsion or suspension tosolidify as particles. Mixing conditions are readily determined by askilled artisan who has read the present specification using knowntechniques, for example, by using an anchor stirrer, homogenizers,colloidal mills, microfluidizers, sonicators, or impellers (mechanicalstirring). Particle size can be varied by changing the amount ofimparted movement. For example, slow stirring will generally produce alarger particle size than will fast stirring. The examples which followprovide ample guidance for one skilled in the art to determineappropriate mixing conditions without undue experimentation.

Microcapsules are formed by a single encapsulation, whereas microspheresare conglomerates of multi-oil droplets embedded in a spherical orsphere-like matrix. The term "primary particle" as used herein refers tomicro- and/or macro-particles produced by either heat inducing(setting), coacervating or cross-linking a polymer-containingemulsification. For convenience, cross-linking, coacervating and thermalsetting will collectively be referred to as "solidifying."

Theoretically, preparation of oleophilic substances in a primarypolymer-containing solution to form an emulsion or suspension can beperformed at any temperature. However, the practical temperature rangefor this step depends on the nature of polymer chosen. For example, inpreparing an HPMC emulsion, the preferred temperature should be betweenroom temperature and no higher than 60° C. The skilled artisan isreadily able to determine an acceptable temperature range based on thecomponents chosen.

The solidification step for making the primary particles is physicallydetermined by the mechanism and process temperature. For instance, ifsolidification is caused by cross-linking, such as with an alginateemulsion cross-linking with calcium ions, temperature may not becritical. That is, processing can be effected at any temperature.However, when HPMC is chosen as the main polymer for the primaryparticles, and heating is the main mechanism utilized to make primaryparticles, temperature becomes important and must be maintained at about60° C. throughout the whole process. Again, these parameters aredeterminable to the skilled artisan, having read the present disclosure.

Primary particles may then be further encapsulated with a secondaryand/or tertiary (depending on whether the primary particles aremicrocapsules or microspheres) polymeric layer by the addition of asecond polymer to the suspension followed by solidifying the secondpolymer (such as cross-linking by adding a cation, or by changing thepH) to form a secondary particle. The term "secondary particle" as usedherein refers to a primary particle which has been further encapsulatedor coated. The term "encapsulated" also includes the term "coated". Ofcourse, multiple primary particles (at least 2) may be encapsulated orcoated to form a single secondary particle.

Although the current method of production first solidifies the primarypolymers by heating to form the primary particles and then simply coatsor chemically cross-links the secondary polymers to form the secondaryparticles, alternate methods of solidifying may be utilized.Additionally, further encapsulations of the secondary particles, such ascoating or polymerization around the secondary particles, may beeffected.

Secondary and tertiary polymers are typically celluloses (e.g.,methylcellulose or hydroxypropyl methylcellulose), cellulose derivatives(e.g., hydroxypropyl methylcellulose phthalate), alginates (e.g., sodiumalginate or propylene glycol alginate), modified starches (e.g.,pregelatinized corn starch or hydroxypropyl starch), calcium lactate,gelatins (e.g., fish gelatin), maltodextrins (e.g., dextrin having about18 dextrose equivalent value, D.E.=18), or acacias. The final mixturemay be sprayed dried or processed by any suitable drying techniques topowder or beadlet form which has high potency, is dry and free-flowing,and is suitable for tableting or encapsulation within soft or hardgelatin capsules. Such powders may also be used in food, animal feed, orother pharmaceutical applications, such as premix, suspension andemulsion.

The addition of secondary and/or tertiary polymer onto the primaryparticles is based on the same principle as described above. The propertemperatures, pH ranges, and ionic strengths for adding the secondand/or third polymer varies depending on the types of materials andmechanisms used.

EXPERIMENTAL DETAIL Example 1 High Potency Vitamin E Acetate UsingMethocel E 15LV as the Primary Polymer, Sodium Alginate As the SecondPolymer, and HPMC 6 cps as the Tertiary Polymer

    ______________________________________                                        INGREDIENTS    FORMULA I A FORMULA I B                                        ______________________________________                                        Vitamin E acetate                                                                            75 + 2% overage.sup.1                                                                     75 + 2% overage.sup.1                                Methocel E 15LV.sup.2 13.0 20.0                                               Kelton LV/CaCloride.sup.3 2.0 2.0                                             Ratio 1:0.5                                                                   HPMC, 6 cps.sup.4 10.0 3.0                                                  ______________________________________                                         .sup.1 Overage is standard in the industry to ensure that the final           product contains at least the given percentage. Therefore, a 2% overage       was added.                                                                    .sup.2 Methocel E15LV refers to a special grade of hydroxypropyl              methylcellulose manufactured by Dow Chemical Co.                              .sup.3 Keltone LV refers to the trade name for sodium alginate from the       Kelco, Division of Merck & Co. Inc.                                           .sup.4 HPMC, 6 cps refers to hydroxypropyl methylcellulose 2910; such as      that manufactured by SHIETSU Co. ("PHARMACOAT 606"). "Cps" is the             viscosity unit "centiopoise," is commonly referred to in the industry, an     is referenced throughout the specification.                              

Procedure

1. Sodium alginate solution (5% w/w) was prepared in a 2 liter (l)beaker as follows:

    ______________________________________                                        Preparation of 5% sodium alginate                                                                 Stirrer                                                     Time Temperature speed                                                        (min.) (° C.) (rpm) Amount Comments                                  ______________________________________                                        0     20                1.27 l                                                                              Add water to beaker and stir                      5 20 1200 66.7 g Add sodium alginate                                           25 2000  Heat suspension to 70° C.,                                       and maintain temperature                                                      and agitation until the                                                       solution is used                                                        ______________________________________                                    

2. Calcium chloride solution (5% by weight) was prepared in a 1 l beakeras follows:

    ______________________________________                                        Preparation of 5% calcium chloride                                              Time    Temperature                                                           (min.) (° C.) Stirrer Amount Comments                                ______________________________________                                        0               --      0.633 l                                                                             Add water to beaker                               1  on  33.3 g Add calcium chloride                                            2 22 on  Stir and maintain                                                        temperature at 70° C. until                                            used                                                                    ______________________________________                                    

3. HPMC, 6 cps solution (12% by weight) was prepared in a 5 l beaker asfollows:

    ______________________________________                                        12% HPMC, 6 cps                                                                                   Stirrer                                                     Time Temperature speed                                                        (min.) (° C.) (rpm) Amount Comments                                  ______________________________________                                        0     21                2.45 l                                                                              Add water to beaker and                               heat to 90° C.                                                     32 90 1000  0.5 kg Slowly add HPMC 6 cps                                          powder with agitation                                                     52 86 200  Addition completed                                                     Remove heating source                                                     82 91 1000 1.22 l Rapidly add cold water                                          (rapid cooling)                                                               Cool to room temperature                                                      while maintaining gentle                                                      agitation until use                                                     ______________________________________                                    

4. Methocel E15LV solution (10%) was prepared using the same procedureas described in step 3. Essentially, Methocel E15LV was dispersed in 90°C. water, stirred and then uniformly dissolved in the water while thetemperature was cooled.

5. Vitamin E acetate (an oil) was added to the Methocel solutionaccording to the above formula, and homogenized using a colloidal milluntil an emulsion having the smallest possible oil droplet size wasreached. Although average droplet size tends to vary, droplets less thanabout 3 μm in diameter are satisfactory for most uses. Typically,average droplets range between about 0.5 and 1 μm in diameter, eventhough smaller diameters are generally preferred. (Duringemulsification, a cooling system was applied to maintain the temperatureat approximately 25° C.).

6. The emulsion was then heated to about 80-90° C. while mixing slowly(at about 200 r.p.m.) with an anchor stirrer.

7. Warm (70° C.) 5% alginate solution was then added and the mixture wasmixed slowly (at about 200 revolutions per minute (r.p.m.) with ananchor stirrer) while maintaining temperature above 70° C.

8. The mixture was maintained at about 70° C. for approximately 15minutes, and then cross-linked by adding 5% calcium chloride solution.

9. HPMC 6 cps 12% solution at room temperature (RT) was added in smallaliquots while maintaining the temperature above 70° C.

10. Water was then added to adjust viscosity to less than about 2,000cps (in this particular instance 1,000 cps) for spray drying.

11. The solution was then spray dried under conventional conditions.

A specific vitamin E emulsion was prepared in a FRYMA processing unit(homogenizer, different types of mixers, and cooling and heating system)manufactured by Fryma, Inc., as follows:

    __________________________________________________________________________    Preparation of the vitamin E emulsion and suspension                          Time                                                                              Temp.                                                                             Anchor                                                                            Colloidal                                                           (min.) (° C.) stirrer mill Dissolver Amount Comments                 __________________________________________________________________________    0   26  on  --   --    6.5 kg                                                                           Add 10% Methocel solution to                                vessel                                                                  10 26 -- -- -- 3.83 kg Add vitamin E acetate to above                               solution                                                                18 27 on on on  Start emulsification                                          23  on on on  Sample 1: particle size of oil                                        droplets 790 nm                                                         28  on on on  Sample 2: particle size of oil                                        droplets 713 nm                                                         33  on on on  Sample 3: particle size of oil                                        droplets 768 nm                                                         33  on -- --  Emulsification ended; begin heating                                   to 85° C. and maintain a proper                                        agitation throughout the whole                                                process                                                                 110 35 on -- --  Add sodium alginate solution (75° C.)                 115 83 on -- --  Mix 15 minutes                                               130 82 on -- --  Add calcium chloride solution                                      (75° C.)                                                         132 85 on -- --  Add HPMC 6 cps solution (75° C.)                      145 85 on -- --  Begin cooling                                                165 82 on -- --  Mix at room temperature                                      195 22 on -- --  Heat up to 75° C.                                     245 19 on -- --  Measure viscosity: 4300 cps                                  255 73 on -- --   21 Add water to adjust viscosity to                               1000 cs                                                               __________________________________________________________________________

Spray dry the above vitamin E suspension using a NIRO spray dryer;operation with air. This spray dryer is manufactured by Niro, Inc.

Example 2A High Potency Vitamin E Acetate Using Methocel E15LV as thePrimary Polymer and HPMCP HP-55S as the Secondary Polymer

    __________________________________________________________________________    INGREDIENTS 85% E                                                                              80% E                                                                             75% E                                                                              70% E                                                                             65% E                                                                              50% E                                      __________________________________________________________________________    Vitamin E acetate                                                                         85   80  75   70  65   50                                           Methocel E15LV 10.0 13.4 16.7 20 23.4 33.4                                    HPMCP grade HP-55S* 5.0 6.6 8.3 10 11.6 16.4                                __________________________________________________________________________     Note: A 2% overage for Vitamin E acetate was used for each formula.           * To dissolve HPMCP, 4.5 ml of 0.5N NaOH per gram of HPMCP was utilized.      Once HPMCP completely dissolved in the alkaline solution, water was added     to adjust the solution to 15% solid content.                             

Procedure

1. HPMCP HP-55S solution (15% by weight) was prepared in a 100 l vesselas follows:

    ______________________________________                                        Preparation of 15% HPMCP HP 55s Solution                                        Time    Temp.                                                                 (min.) (° C.) Stirrer Amount Comments                                ______________________________________                                        0     16      on      14.94 l                                                                              Add water into the vessel                          5 15 on   300 g Add sodium hydroxide slowly                                   10 16 on  Addition ended                                                      15  on  3.32 kg Add HPMCP HP-55S                                                  powder to above solution                                                      with agitation                                                            35 14 on  Addition ended, start heating                                       215 65 on  3.57 l Add 70° C. hot water                                     Stir the solution until use                                             ______________________________________                                    

2. Methocel E15LV solution (10%) was prepared as in Example 1.

3. Vitamin E acetate was added to the Methocel solution according to theabove formulas and homogenized to produce an emulsion as in Example 1.

4. The resulting emulsion was heated to 80-90° C. with slow (200 r.p.m.)mixing with an anchor stirrer.

5. An amount of warm (70° C.) 15% HPMCP solution was added. The amountadded corresponded to the amount recited in percentage table shownabove.

6. The temperature of above mixture was kept at about 80° C. andcross-linked by adding HCl (0.1 N), with mixing, to shift the pH toapproximately 5 (about 4.9-5.2).

7. The cross-linked solution was allowed to equilibrate forapproximately 45 minutes.

8. The resulting cross-linked solution was then spray dried at theconditions shown below to form a powder.

    __________________________________________________________________________    Spray drying of the vitamin E suspension                                        The suspension was pumped from the FRYMA processing unit to the spray       tower by a                                                                      gear pump and then atomized by a rotary atomizer from Niro, Inc.                Set     Set     Set                                                                                         Inlet Inlet outlet Outlet Pressure                                          Pressure In at air                              Time Temp. Temp. Temp. Temp. Tower Tower flow in                              (min.) (° C.) (° C.) (° C.) (° C.) in mbar                                      in mbar m.sup.3 /n Comments                   __________________________________________________________________________    0   180     100     -5          Start up lower                                  50 180 181 100 101 -5 -3 1500 Start spray drying                              60 180 181 100 100 -5 -3 1500                                                 62        Spray drying ended                                                __________________________________________________________________________

The "Set Pressure Tower" is the setting for the equilibrium condition inthe dryer. In contrast, the "Pressure Tower" is the actual pressurereached in the dryer during spray drying.

Example 2B High Potency Vitamin E Acetate Using Methocel E15LV as thePrimary Polymer and Fish Gelatin, Maltodextrin, Pregelatinized CornStarch, Calcium Lactate, or Hydroxypropyl Starch as the SecondaryPolymer

Following the procedure in Example 2A (with HPMCP being replaced byanother secondary polymer), several different secondary polymers wereevaluated as follows:

    __________________________________________________________________________              Fish      Preglatinized                                                                        Calcium                                                                            Hydroxypropyl                                    Gelatin Maltrin Corn Starch Lactate Starch                                   INGREDIENTS 75% E 75% E 75% E 75% E 75% E                                   __________________________________________________________________________    Vitamin E Acetate                                                                       75   75   75     75   75                                              Methocel E15LV 16.7 16.7 16.7 16.7 16.7                                       Fish Gelatin 8.3 --  --  --  --                                               Maltrin M180.sup.1 --  8.3 -- -- --                                           Pregelatinized Corn                                                           Starch -- --  8.3 -- --                                                       Calcium Lactate -- -- --  8.3 --                                              Hydroxypropyl Starch -- -- -- --  8.3                                       __________________________________________________________________________     .sup.1 Brand of maltodextrin (D.E. = 18).                                

Analysis of the five secondary polymers provided the following resultsusing standard test procedures:

    ______________________________________                                                  Fish  Maltrin PreGel         HP                                       Gelatin M180 Starch CaLactate Starch                                        ______________________________________                                        Flow   sec./100 g                                                                             27      23    28    17     39                                   (Agway)                                                                       Density g/ml 0.34 0.39 0.33 0.50 0.34                                         Tapped g/ml 0.39 0.44 0.38 0.56 0.39                                          Density                                                                       Moisture % 1.3 1.0 2.8 0.8 1.0                                                Color W1E313 37.87 54.26 51.43 53.65 50.10                                     Y1E313 13.22 9.18 9.96 9.12 9.94                                             Static observed High Medium Low Medium Very                                         High                                                                    Free Oil.sup.5 % 2.4 1.6 2.3 2.9 2.2                                        ______________________________________                                         .sup.5 Free Oil refers to the percentage of unencapsulated vitamin E, and     was determined as follows:                                               

Procedure for Measuring Free Oil on Powder Surface

Procedure for Preparing Sample Solution

1. Transfer 0.250 g of powder (vitamin E 75%) to a suitable container.

2. Add 43.0 g of light mineral oil (Fisher).

3. Shake on a mechanical shaker at medium speed for 15 minutes.

4. Pass through a 0.45 μm filter.

5. Measure the UV absorption of the filtrate at 285 nm to determine theabs(sample). Compare against known vitamin E acetate standard (Std).

Procedure for Preparing Standard Solution

1. Weigh 150 mg vitamin E oil standard in a suitable container.

2. Add 86.0 g light mineral oil to above container.

3. Mix using a mechical shaker at medium speed for 15 minutes.

4. Remove 2.5 g of above solution and transfer to an appropriatecontainer.

5. Add 43.0 g of light mineral oil to the container and shake for anadditional 15 minutes.

6. Measure the u.v. absorbtion of above solution at 285 nm to determineabs(Std.).

Calculations: ##EQU1## % Free Oil in powder (% unencapsulated vitaminE)=X/(0.25×0.75)×100

Procedure for Evaluating Powder Suitability for Tabletting

The powders of the subject invention are useful in producing antioxidanttablets. To demonstrate their suitability and tabletting performance inantioxidant tablets, tablets were prepared at 4,000 lb pressure using arotary press.

    __________________________________________________________________________    TABLETTING PERFORMANCE OF VITAMIN E75% POWDERS IN                               ANTIOXIDANT TABLETS AT 4000 LB PRESSURE USING ROTARY PRESS                  __________________________________________________________________________    Ejection Force                                                                        lbs  47   40   41   38   43                                             Hardness Avg scu 15 17.1 16.9 12.3 12.9                                     Range        11.7-16.9                                                                          15.6-18.3                                                                          15.8-18                                                                            11.1-13.6                                                                          11.8-13.6                                    Disintegration                                                                        minutes                                                                            15   15   20   14   14                                             Friability % 0.03 0.07 0.09 0.08 0.09                                       __________________________________________________________________________

The above results were obtained using the following antioxidant formula:

    __________________________________________________________________________    ANTIOXIDANT FORMULA                                                             USING VITAMIN E75, BETATAB R AND C-90 GLOBAL                                              claim                                                                              %              kg/90 kg                                      Ingredients tablet overage mg/tab % Batch                                   __________________________________________________________________________    BetaTab R 7.5%                                                                               6 mg                                                                              35   108  11.55                                                                              10.395                                        (Beta Carotene 7.5% Beadlets)                                                 Vitamin C-90 Global 250 mg 5 292 31.23 28.107                                 Vitamin E 75% 200 IU 5 280 29.95 26.955                                       Microcel C   97 10.37 9.333                                                   (Calcium Silicate)                                                            Avicel PH 102   56 5.99 5.373                                                 (Microcrystalline cellulose)                                                  Polyplasdone XL   97 10.37 9.333                                              (Crospovidone)                                                                Cab-O-Sil   5 0.54 0.486                                                      (Colloidal Silicon Dioxide)                                                   TOTAL   935 100 90                                                          __________________________________________________________________________

Example 3 High Potency E Formula III Containing Acacia

    ______________________________________                                        Ingredients        75% E   80% E                                              ______________________________________                                        1. Vitamin E Acetate                                                                             75.0*   80.0*                                                2. HPMC E15LV 15.0 12.0                                                       3. Acacia 10.0 8.0                                                            Total 100.0% 100.0%                                                         ______________________________________                                         *Additional 2% overage was added.                                        

Procedure

1. Gum acacia solution (20% by weight) was prepared in a 4 l beaker asfollows:

    ______________________________________                                        Preparation of 20% gum acacia                                                   Time                                                                          (min.) Temp. (° C.) Stirrer Amount Comments                          ______________________________________                                        0      21° C.                                                                           on         2 l  Add water into beaker                          151 39° C. on, slow 0.5 kg Add gum acacia                              175 36° C. on, fast  Addition completed                                190 37° C. on, fast  Begin heating                                     208 63° C. on, slow                                                    279 71° C. --  Add to emulsion                                       ______________________________________                                    

2. 10% Methocel E 15LV solution was prepared as in Example 1.

3. Vitamin E acetate was added to Methocel solution according to theabove formulas and homogenized to produce an emulsion as in Example 1.

4. The resulting emulsion was heated to 80-90° C. with slow (200 r.p.m.)agitation.

5. An appropriate amount of 20% acacia solution from step 1 was added.

6. The mixture from above was blended with gentle agitation for anadditional 15 minutes while the temperature were maintained at 70-90° C.

7. Spray the vitamin E suspensions at the following conditions.

    __________________________________________________________________________    Spray drying of the vitamin E suspension                                        The suspension was pumped from the FRYMA processing unit to the spray       tower by a                                                                      gear pump and then atomized by a rotary atomizer manufactured by Niro,      Inc.                                                                              Set     Set     Set     In at                                                Inlet Inlet outlet Outlet Pressure Pressure air                              Time Temp. Temp. Temp. Temp. Tower Tower flow in                              (min.) (° C.) (° C.) (° C.) (° C.) in mbar                                      in mbar m.sup.3 /n Comments                   __________________________________________________________________________    0   180     100     -5          Start up lower*                                 50 180 181 100 101 -5 -3 1500 Start spray drying                              60 180 181 100 100 -5 -3 1500                                                 62        Spray drying ended                                                __________________________________________________________________________     *Shorthand for start up the spray dryer from a lower inlet temperature. I     is standard procedure to start up a spray dryer at low temperature, then      gradually increase the inlet temperature to reach a proper outlet             temperature, and to establish an equilibrium condition.                  

Example 4 30% Vitamin A Products Using Hydroxypropyl Methylcellulose asthe Primary Polymer, and Sodium Alginate, HPMCP HP-55, or Acacia as theSecondary Polymer

    ______________________________________                                        Ingredient     Formula I Formula II                                                                              Formula III                                ______________________________________                                        Vitamin A Palmitate                                                                          30.0 + 2.5*                                                                             30.0 + 2.5*                                                                             30.0 + 2.5*                                  Butylated Hydroxyanisole 1.0 1.0 1.0                                          (BHA)                                                                         Butylated Hydroxytoluene 3.0 3.0 3.0                                          (BHT)                                                                         Methocel E15LV 50.8 42.4 50.8                                                 HPMCP, HP-55S --  21.1 --                                                     Acacia -- --  12.7                                                            Sodium Alginate 3.4 -- --                                                     Calcium Chloride 1.7 -- --                                                    PHARMACOAT 606 7.6 -- --                                                    ______________________________________                                         Note: *% Overage                                                         

Procedure

Formulation I

Composition

    ______________________________________                                        Material           content (%)                                                                             weight (kg)                                      ______________________________________                                        Vitamin A palmitate 1.7 MIU/g                                                                    32.47     1.30                                               BHA 1 0.04                                                                    BHT 3 0.12                                                                    METHOCEL E15LV premium 50.82 2.03                                             Sodium alginate 3.39 0.136                                                    Calcium chloride 1.69 0.068                                                   PHARMACOAT 606 7.62 0.305                                                   ______________________________________                                    

General

All the solutions were prepared using degassed deionized water undernitrogen. Vitamin A palmitate was shielded from light.

Preparation of a 12% solution of METHOCEL E15LV

Water (8 l) was heated to 85° C. METHOCEL E15LV powder (2.03 kg) wasslowly added into the water while mixing with rapid agitation until auniform suspension was obtained and thoroughly dispersed. Additionalcold water (6.89 l) was quickly added to the suspension and thetemperature was cooled to 25° C.

Preparation of a 5% solution of sodium alginate

Sodium alginate powder (0.136 kg) was added into 2.58 liters of coldwater with proper agitation and heated to 80-90° C. The solution waskept at 70° C. until used.

Preparation of a 5% solution of calcium chloride

Calcium chloride (0.068 kg) was dissolved in 1.29 l of water. Thesolution was kept at room temperature until used.

Preparation of a 12% solution of PHARMACOAT 606

Water (0.75 l) was heated to 90° C. PHARMACOAT 606 powder (0.305 kg) wasslowly added into the water while mixing with proper agitation until auniform suspension was formed. Cold water (1.50 l) was added quickly tothe suspension and the temperature was cooled to 25° C. The solution wasmaintained at room temperature with gentle agitation until used.

Preparation of the emulsion/suspension

BHA (0.04 kg) and 0.12 kg BHT were added to 1.3 kg vitamin A palmitateand mixed until a clear solution was formed. The resulting solution wasadded to the METHOCEL E15LV solution and emulsified for 30 minutes withthe colloidal mill. (The oil droplet size measured using a MALVERNAutosizer was 757 nm). The emulsion was then heated to 75° C. whileslowly mixing (200 r.p.m.) with an anchor stir bar to form a suspension.The 70° C. sodium alginate solution was added to the suspension andstirred for 15 minutes. Calcium chloride solution was added, and themixture was cooled. PHARMACOAT solution was added at room temperatureand mixed for 10 minutes. The mixture was then heated to 65° C. whilemixing slowly with an anchor stir bar. (the suspension had a viscosityof 11,400 cps/65° C.). The suspension was then diluted with 2 l hotwater to adjust the viscosity to 2,500 cps/65° C.

Spray drying

See below (spray dry results are shown in FIGS. 6-9).

Formulation II

Composition

    ______________________________________                                        Material           content (%)                                                                             weight (kg)                                      ______________________________________                                        Vitamin A palmitate 1.7 MIU/g                                                                    32.47     1.46                                               BHA 1 0.045                                                                   BHT 3 0.135                                                                   METHOCEL E15LV premium 42.44 1.91                                             HPMCP 55 21.09 0.95                                                         ______________________________________                                    

General

All the solutions were prepared using degassed deionized water undernitrogen. Vitamin A palmitate was shielded from light.

Preparation of a 12% solution of METHOCEL E15LV

Water (8 l) was heated to 85° C. METHOCEL E15LV powder (2.03 kg) wasslowly added into the water while mixing with rapid agitation until auniform suspension was obtained and thoroughly dispersed. Additionalcold water (6.89 l) was quickly added to the suspension and thetemperature was cooled to 25° C.

Preparation of a 15% solution of HPMCP

HPMCP powder (0.95 kg) was added to 4.28 l of 0.5 N NaOH with properagitation and heated to 70° C. Hot (70° C.) water (1.1 l) was addedafter the powder completely dissolved. The solution was kept at 70° C.until used.

Preparation of the emulsion/suspension

BHA (0.045 kg) and 0.135 kg BHT were added to 1.46 kg vitamin Apalmitate and mixed until a clear solution was formed. The solution wasadded to the METHOCEL E solution and emulsified for 30 minutes using acolloidal mill. The oil droplet size measured using a particle sizeanalyzer (MALVERN Autosizer 2C manufactured by Malverne Instruments,Inc.) was 888 nm. Then, the emulsion was heated to 75° C. while slowlystirring (200 r.p.m.) with an anchor stir bar to form a suspension. The70° C. HPMCP solution was added to the suspension and continuouslystirred with an anchor agitator. The pH was adjusted to 6.9 with 0.5 lof 1 N NaOH (pH before: 5.28). The resulting suspension had a viscosityof 500 cps/70° C.

Spray drying

See below.

Formulation III

Composition

    ______________________________________                                        Material           content (%)                                                                             weight (kg)                                      ______________________________________                                        Vitamin A palmitate 1.7 MIU/g                                                                    32.47     1.46                                               BHA 1 0.045                                                                   BHT 3 0.135                                                                   METHOCEL E15LV premium 50.82 2.29                                             Gum acacia 12.7 0.58                                                        ______________________________________                                    

General

All solutions were prepared using degassed deionized water undernitrogen. Vitamin A palmitate was shielded from light.

Preparation of a 10% solution of METHOCEL E

Water (6.2 l) was heated to 85° C. METHOCEL E15LV powder (2.29 kg) wasslowly added into the water while mixing with rapid agitation until auniform suspension was obtained. Additional cold water (14.41 l) wasquickly added to the suspension and the temperature was cooled to 25° C.

Preparation of a 20% solution of gum acacia

Gum acacia powder (0.58 kg) was dissolved to 2.32 l cold water andheated to 70° C. The solution was kept at 70° C. until used.

Preparation of the emulsion/suspension

BHA (0.045 kg) and 0.135 BHT were added to 1.46 kg vitamin A palmitateand mixed until a clear solution was formed. The solution was added tothe METHOCEL E solution and emulsified for 30 minutes with the colloidalmill. The oil droplet size measured using MALVERN Autosizer 2C was 854nm. The emulsion was then heated to 75° C. while mixing with an anchorbar to form a suspension. The 70° C. gum acacia solution was added tothe suspension and stirred with an anchor agitator. The pH was adjustedto 7.2 with 40 ml of 0.5 N NaOH (pH before: 6.37). The resultingsuspension had a measured viscosity of 1060 cps/70° C.

Spray drying

See below.

Spray Drying Conditions for Formulations I, II and III

    ______________________________________                                                                    Inlet Outlet                                                                              Inlet                                   Formu- Feed    Air Air Air Wheel                                              lation Temp. Viscosity  Temp. Temp. Flow Speed                                Number (° C.) (cps) pH (° C.) (° C.) m.sup.3 /h                                                     (rpm)                            ______________________________________                                        I     65      2,500/65° C.                                                                     --  165   100   1,500                                                                              8,500                              II 70   500/70° C. 6.9 165 100 1,500 8,500                             III 70 1,060/70° C. 7.2 160 100 1,500 8,500                          ______________________________________                                    

2% silicic acid (type FK 320 DS) was added in each trial. Pressureinside the tower was always about -4 mbar.

The subject invention has been described in terms of its preferredembodiments. However, one skilled in the art will recognize variousalternative embodiments having read the specification. These variationsare to be considered within the scope and spirit of the invention whichis only to be limited by the claims which follow and their equivalents.

What is claimed is:
 1. A powder composed of particles, the particlescomprising an oleophilic substance encapsulated in a water solublecellulose polymer, wherein the oleophilic substance is from aboutsixty-five percent to about eighty-five percent by weight of the powder,produced by:a) incorporating an oleophilic substance into an aqueoussolution having a cellulose primary polymer dissolved therein, to forman aqueous mixture of the oleophilic substance in the solution, whereinthe oleophilic substance in the mixture excluding overage is from aboutsixty-five percent to about eighty-five percent of the combined weightof the oleophilic substance and the polymer in the mixture; b) heatsetting the primary polymer under mixing conditions while the primarypolymer is in the aqueous mixture, to encapsulate the oleophilicsubstance within the primary polymer and form a primary particle in theaqueous mixture; and c) drying the aqueous mixture produced in step b)to yield the powder.
 2. The powder of claim 1, wherein the celluloseprimary polymer is selected from the group consisting of methylcelluloseand hydroxypropyl methylcellulose.
 3. The powder of claim 1, wherein theoleophilic substance is a fat-soluble vitamin.
 4. The powder of claim 3,wherein the fat-soluble vitamin is selected from the group consisting ofvitamins A, D, E and K.
 5. The powder of claim 4, wherein thefat-soluble vitamin is vitamin E.
 6. The powder of claim 2, wherein thecellulose primary polymer is hydroxypropyl methylcellulose.
 7. A powdercomposed of particles, the particles comprising an oleophilic substanceencapsulated in a water soluble cellulose polymer, wherein theoleophilic substance is from about sixty-five percent to abouteighty-five percent by weight of the powder, produced by:a)incorporating an oleophilic substance into an aqueous solution having acellulose primary polymer dissolved therein, to form an aqueous mixtureof the oleophilic substance in the solution; b) heat setting the primarypolymer under mixing conditions while the primary polymer is in theaqueous mixture, to encapsulate the oleophilic substance within theprimary polymer and form a primary particle in the aqueous mixture; c)adding a secondary polymer to the aqueous mixture under mixingconditions to further encapsulate at least one primary particle withinthe secondary polymer, wherein the oleophilic substance in the mixtureexcluding overage is from about sixty-five percent to about eighty-fivepercent of the combined weight of the oleophilic substance, the primarypolymer and the secondary polymer in the mixture; and d) drying theaqueous mixture produced in step c) to yield the powder.
 8. The powderof claim 7, wherein the secondary polymer is selected from the groupconsisting of cellulose, cellulose derivatives, alginate, acacia,gelatin, maltodextrin, calcium lactate, and modified starches.
 9. Thecomposition of claim 8, wherein the cellulose derivative is selectedfrom the group consisting of methylcellulose and hydroxypropylmethylcellulose.
 10. The powder of claim 8, wherein the cellulosederivative is hydropropylmethyl cellulose phthalate.
 11. The powder ofclaim 8, wherein the secondary polymer is a gelatin which is a fishgelatin.
 12. The powder of claim 8, wherein the secondary polymer ismaltodextrin.
 13. The powder of claim 12, wherein the maltodextrin has adextrose equivalent value of about
 18. 14. The powder of claim 8,wherein the secondary polymer is a modified starch selected from thegroup consisting of pregelatinized corn starch and hydroxypropyl starch.15. The powder of claim 7, wherein the secondary polymer encapsulates atleast two primary particles.
 16. The powder of claim 7, wherein thecellulose primary polymer is selected from the group consisting ofmethylcellulose and hydroxypropyl methylcellulose.
 17. The powder ofclaim 16, wherein the primary polymer is hydroxypropyl methylcellulose.18. The powder of claim 7, wherein the oleophilic substance is afat-soluble vitamin.
 19. The powder of claim 18, wherein the fat-solublevitamin is selected from the group consisting of vitamins A, D, E and K.20. The powder of claim 19, wherein the fat-soluble vitamin is vitaminE.
 21. The powder of claim 1, wherein the oleophilic substance is fromabout seventy percent to about eighty-five percent by weight of thepowder; and the oleophilic substance in the mixture excluding overage isfrom about seventy percent to about eighty-five percent of the combinedweight of the oleophilic substance and the polymer in the mixture. 22.The powder of claim 21, wherein the oleophilic substance is from aboutseventy-five percent to about eighty-five percent by weight of thepowder; and the oleophilic substance in the mixture excluding overage isfrom about seventy-five percent to about eighty-five percent of thecombined weight of the oleophilic substance and the polymer in themixture.
 23. The powder of claim 22, wherein the oleophilic substance isfrom about eighty percent to about eighty-five percent by weight of thepowder; and the oleophilic substance in the mixture excluding overage isfrom about eighty percent to about eighty-five percent of the combinedweight of the oleophilic substance and the polymer in the mixture. 24.The powder of claim 7, wherein the oleophilic substance is from aboutseventy percent to about eighty-five percent by weight of the powder;and the oleophilic substance in the mixture excluding overage is fromabout seventy percent to about eighty-five percent of the combinedweight of the oleophilic substance, the primary polymer and thesecondary polymer in the mixture.
 25. The powder of claim 24, whereinthe oleophilic substance is from about seventy-five percent to abouteighty-five percent by weight of the powder; and the oleophilicsubstance in the mixture excluding overage is from about seventy-fivepercent to about eighty-five percent of the combined weight of theoleophilic substance, the primary polymer and the secondary polymer inthe mixture.
 26. The powder of claim 25, wherein the oleophilicsubstance is from about eighty percent to about eighty-five percent byweight of the powder; and the oleophilic substance in the mixtureexcluding overage is from about eighty percent to about eighty-fivepercent of the combined weight of the oleophilic substance, the primarypolymer and the secondary polymer in the mixture.
 27. A powder composedof particles, the particles comprising an oleophilic substanceencapsulated in a water soluble cellulose polymer, said powder producedby:a) incorporating an oleophilic substance into an aqueous solutionhaving a primary polymer which is hydroxypropyl methylcellulosedissolved therein, to form an aqueous mixture of the oleophilicsubstance in the solution; b) heat setting the primary polymer undermixing conditions while the primary polymer is in the aqueous mixture,to encapsulate the oleophilic substance within the primary polymer andform a primary particle in the aqueous mixture; c) adding a secondarypolymer to the aqueous mixture under mixing conditions to furtherencapsulate at least one primary particle within the secondary polymer;and d) drying the aqueous mixture produced in step c) to yield thepowder.
 28. A powder composed of particles, the particles comprising anoleophilic substance encapsulated in a water soluble cellulose polymer,said powder produced by:a) incorporating an oleophilic substance into anaqueous solution having a primary polymer which is hydroxypropylmethylcellulose dissolved therein, to form an aqueous mixture of theoleophilic substance in the solution; b) heat setting the primarypolymer under mixing conditions while the primary polymer is in theaqueous mixture, to encapsulate the oleophilic substance within theprimary polymer and form a primary particle in the aqueous mixture; andc) drying the aqueous mixture produced in step b) to yield the powder.29. A powder composed of particles, the particles comprising anoleophilic substance encapsulated in a water soluble cellulose polymer,said powder produced by:a) incorporating an oleophilic substance into anaqueous solution having a cellulose primary polymer dissolved therein,to form an aqueous mixture of the oleophilic substance in the solution;b) heat setting the primary polymer under mixing conditions while theprimary polymer is in the aqueous mixture, to encapsulate the oleophilicsubstance within the primary polymer and form a primary particle in theaqueous mixture; c) adding a secondary polymer to the aqueous mixtureunder mixing conditions to further encapsulate at least one primaryparticle within the secondary polymer, wherein said secondary polymer istaken from the group consisting of hydropropyl methylcellulosephthalate, fish gelatin, maltodextrin, pregelatenized corn starch andhydroxypropyl starch; and d) drying the aqueous mixture produced in stepc) to yield the powder.